Immunosuppressants Flashcards Preview

systemic pharmaco > Immunosuppressants > Flashcards

Flashcards in Immunosuppressants Deck (20):
1

Uses of immunosuppressants (4)

1. Solid organ/tissue transplantation rejection
2. Graft vs Host Disease
3. Autoimmune Diseases (RA, SLE, MS, CD)
4. Inflammatory Diseases

2

Classes of immunosuppressants & examples (7)

1. Calcineurin inhibitors (Cyclosporin A, Tacrolimus (FK506) )
2. mTOR inhibitors (Sirolimus (Rapamycin) )

Cytotoxic agents
3. Azathioprine
4. Mycophenolate mofetil (MMF), mycophenolate sodium (MPS)

5. Polyclonal antibodies (Atgam, thymoglobulin)
6. Monoclonal antibodies & fusion proteins (Muromonab-CD3 (OKT3) )
7. Rho (D) immune globulin

3

Mechanism of action of calcineurin inhibitors

T cell-selective immunosuppressants
1. CSA binds to ubiquitous cytosolic cyclophilin - CSA:cyclophilin complex binds & inhibits calcineurin
2. Prevents translocation of transcription factor NF-AT - remains phosphorylated, cannot enter nucleus
3. Inhibits cytokine gene transcription & synthesis
4. Inhibits primarily T cell proliferation, but also B cell & CTL

- FK506 binds to ubiquitous cytosolic immunophilin (FKBP)

4

Uses of calcineurin inhibitors (5)

1. Transplants - kidney, pancreas, liver, cardiac
2. Uveitis
3. Rheumatoid Arthritis
4. Psoriasis
5. Asthma

5

Toxicity of calcineurin inhibitors (7)

1. Nephrotoxicity
2. Hyperglycemia
3. Hyperlipidemia
4. Increased cancer risk
5. Hypertension (CSA)
6. Gum hyperplasia (CSA)
7. Neurotoxicity (tacrolimus)

6

Mechanism of action of mTOR inhibitors

1. Sirolimus binds to FKBP-12 in the cytoplasm - Sirolimus:FKBP complex - binds & inhibits mTOR (Ser/Thr kinase)
2. Inhibits activity of 70 kDa S6 kinase, activity of 4E-BP1, growth arrest from GI to S phase
3. Inhibits cytokine-mediated proliferation of T & B cells

7

Uses of mTOR inhibitors (2)

1. Anti-proliferative & anti-angiogenesis activities
2. Eluting coronary stents to prevent restenosis

8

Toxicity of mTOR inhibitors (4)

1. Hyperlipidemia
2. Thrombocytopenia
3. Delayed wound healing
4. Mouth ulcers

9

Mechanism of action of azathioprine

1. Converted to 6-mercaptopurine (6-MP) and then to active metabolite 6-thioguanine (6TG)
2. Can integrate into DNA
(A) Structural analog/antimetabolite - impedes DNA synthesis
(B) formation of thioinosinic acid - inhibits de novo purine synthesis - decreased lymphocyte proliferation

10

Uses of azathioprine (1)

1. Renal transplant/other autoimmune disorders
- Triple therapy: Steroid + calcineurin inhibitor + azathioprine

11

Toxicity of azathioprine (2)

1. Bone marrow depression (leukopenia, anemia, thrombocytopenia, bleeding)
2. Drug interactions: allopurinol inhibits xanthine oxidase which metabolizes 6-MP to an inactive metabolite - accumulation of azathioprine/6-MP - toxicity

12

Mechanism of action & uses of MMF/MPS

1. Converted to active metabolite mycophenolic acid
2. Inhibits de novo pathway of purine synthesis by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) - preferentially inhibits type II (inducible) over type I (resting)

- more selective anti-proliferative effects for T/B cells
- suppresses antibody formation by B cells
- inhibits recruitment of leukocytes to graft sites

13

Toxicity of MMF/MPS (4)

1. Diarrhea
2. Neutropenia
3. Anemia
4. Hypertension

less bone marrow depression & GI toxicity than azathioprine

14

Mechanism of action of polyclonal antibodies

1. Non-selective purified IgG targeted at T & B lymphocytes, NK cells, MHC class I & II antigens, co-stimulatory molecules
2. Opsonisation & complement dependent cytotoxicity, ADCC, depletion of T-lymphocytes, cross linking of TCR to induce anergy

15

Uses of polyclonal antibodies

1. Immune globulin intravenous (IGIV) - normalize patients immune network in autoimmune disorders, AIDS, bone marrow transplants

16

Toxicity of polyclonal antibodies

1. First dose effect - cytokine release syndrome (fever, chill, hypotension), thrombocytopenia, leukopenia, serum sickness, development of anti-foreign IgG antibodies, histiocytic lymphoma at site of injection

17

Mechanism of action of monoclonal antibodies

IgG2a subtype directed against CD3-TCR complex, most selective for T lymphocytes - T cell depletion/decreased activity

18

Toxicity of monoclonal antibodies (5)

1. Development of human anti-mouse Ab
2. Anaphylaxis
3. Serum sickness
4. First dose symptoms (cytokine release syndrome)
5. Increased risk of infection/malignancies

19

Mechanism of action & uses of Rho (D) IgG

Human IgG against Rho(D) antigen on RBC

Prevents Rh hemolytic disease of the newborn
- primary Ab response can be blocked if administered at time of exposure
- mother's own Ab response suppressed, disease for next child prevented

20

Toxicity of Rho (D) IgG

local discomfort, temperature rise